OBJECTIVE : To review the current support and treatment strategies
of the acute respiratory distress syndrome.SOURCES OF DATA: Original data from our research laboratory and from
representative scientific articles on acute respiratory distress syndrome and
acute lung Injury searched through Medline.SUMMARY OF THE FINDINGS: Despite advances in the understanding of the
pathogenesis of acute respiratory distress syndrome, this syndrome still results
in significant morbidity and mortality. Mechanical ventilation, the main therapeutic
modality for acute respiratory distress syndrome, is no longer considered simply
a support modality, but a therapy capable of influencing the course of the disease.
New ventilation strategies, such as high-frequency oscillatory ventilation appear
to be promising. This text reviews the current knowledge of acute respiratory
distress syndrome management, including conventional and nonconventional ventilation,
the use of surfactant, nitric oxide, modulators of inflammation, extracorporeal
membrane oxygenation and prone position.CONCLUSIONS: The last decade was marked by significant advances, such
as the concept of protective ventilation for acute respiratory distress syndrome.
The benefit of alternative strategies, such as high frequency oscillatory ventilation,
the use of surfactant and immunomodulators continue to be the target of study.

Acute respiratory
distress syndrome (ARDS) is an entity marked by a significant inflammatory response
to a local (pulmonary) or remote (systemic) insult which invariably results
in hypoxemia and marked alterations to pulmonary mechanics. By definition four
clinical criteria must be met to establish a diagnosis of ARDS1:
1) Acute disease onset, 2) bilateral pulmonary infiltrates on chest x-ray, 3)
pulmonary capillary wedge pressure < 18 mmHg or absence of clinical
evidence of left atrial hypertension, and 4) ratio between arterial oxygen partial
pressure (PaO2) and the fraction of inspired oxygen (FiO2)
< 200. Patients that meet criteria 1 to 3, but exhibit a PaO2
/ FiO2 ratio >200 and < 300 are defined as having Acute
Lung Injury (ALI), a process physiopathologically similar to ARDS but of lesser
clinical severity. Based on the above criteria, it is estimated that ARDS has
an incidence of 13.5 cases per 100,000 people and that ALI affects 17.9 of every
100,000 people2. Despite significant advances in general intensive
care therapies, the dramatic alterations that are characteristic of ARDS are
associated with an elevated mortality, varying between 35% and 71%3-5.

Despite having first been
described several decades ago6 and being a significant causer of
morbidity and mortality in pediatric intensive care units all over the world,
ARDS has no specific pharmacological treatment. However, advances in the understanding
of the pathogenesis and pathophysiology of ARDS over the years have resulted
in the development of a series of support therapies capable of having an impact
on the outcome of patients affected by this pathology (Table 1).

Despite having been
successful in an experimental laboratory environment, many of the methods available
for the management of ARDS have not been shown effective or have not yet been
properly tested in clinical practice. This is primarily due to the fact that
patients with ARDS form an extremely heterogeneous population, who needs to
be evaluated in studies of large samples, requiring significant resources and
a large capacity for integration among participating centers. The availability
of clinical data specific to the pediatric ARDS population is even more limited
due to the almost non-existence of controlled studies in this population. This
being the case, many of the strategies employed for the management of pediatric
ARDS and their indications have been adapted or inferred from studies of adult
patients.

ARDS treatment
strategies

Control of
the causative factor

While ARDS has no
specific treatment, many of the factors causing and perpetuating the disease
process can be treated or controlled. For example, patients with hypovolemic
shock should be quickly identified and treated with rapid volumetric replacement,
in order to minimize the impact on the evolution and maintenance of ARDS. Similarly,
patients with infectious acute abdomen should be treated with antibiotics and
early surgical intervention when indicated. Patients with septic shock or pneumonia
that evolve to ARDS should be promptly treated with intravascular expansion
and antibiotics, since the treatment of the infectious factor and hemodynamic
control are fundamental to the success of managing the subsequent pulmonary
pathology.

Controlled oxygen exposure

By definition, patients with ARDS exhibit significant hypoxemia (PaO2/FiO2
< 200)1. For this reason, oxygen is indicated for the management
of the initial phase of the acute respiratory insufficiency. Severe hypoxemia
in patients with ARDS is due to the intrapulmonary shunt, in which unventilated
lung zones that result from edema, atelectasis or consolidation continue to
receive blood supply, despite being incapable of participating in its oxygenation.
Oxygen therapy, via mask, tent or non-invasive ventilation apparatus is capable
of producing symptomatic improvement during the initial phase of acute respiratory
failure. However, the rapid natural progression of ARDS with diminishing pulmonary
compliance, increased exertion of respiratory muscles and subsequent exhaustion
means that oxygen therapy only has value as a temporary symptom relief measure
until mechanical ventilation is introduced. The great majority of patients that
meet diagnostic criteria for ARDS cannot be managed exclusively with oxygen
therapy, and will require mechanical ventilation. The health care professional
who understands the pathophysiologic process of ARDS should recognize that a
patient that meets diagnostic criteria and requires an accelerated escalation
in oxygen therapy will need mechanical ventilation. Oxygen therapy should not
delay the institution of ventilatory support, since intubation and initiation
of mechanical ventilation for ARDS should be an elective decision made before
the patient develops full-blown respiratory failure.

The administration of oxygen, while simple, is not free from adverse effects.
Continuous exposure to high concentrations of oxygen (FiO2>
0.6) is capable of causing pulmonary injury, even in the absence of a pre-existing
lesion7. Pulmonary injury due to oxygen toxicity is the result of
free radicals and reactive oxygen species that are spontaneously generated in
hyperoxic environments or from the activation of neutrophils and alveolar macrophages8,9.
The normal lung deals with oxidative insults by means of a series of enzymes
(superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase)
or antioxidants (vitamins C and E, albumin, etc.), and is capable of tolerating
elevated oxygen concentrations for a number of days. However, an injured lung
exposed to moderate concentrations of oxygen (which would not be harmful to
a normal lung) can further aggravate pulmonary tissue damage even when the exposure
is limited to just a few hours8. This phenomenon occurs, presumably,
due to an imbalance between oxidative stimuli and antioxidant protective mechanisms
found in acute lung injury states.

Mechanical ventilation

Mechanical ventilation remains the primary support technique for ARDS and
is indicated in the vast majority of cases10. Nonetheless, the indications
for mechanical ventilation in patients with ARDS are, to a certain extent, vague,
based on clinical findings (dyspnea, tachypnea, use and fatigue of accessory
muscles, diaphoresis, poor perfusion, etc.), laboratory findings (acidosis,
hypoxemia, hypercapnia) and radiological findings (worsening alveolar infiltrates).
An attempt at making the criteria for the institution of mechanical ventilation
for ARDS more objective is the so-called "rule of 50s", in which a PaO2
< 50 torr and a PaCO2 > 50 torr with a FiO2 of 50%
characterize patients likely to require ventilatory support. These criteria,
however, identify patients in extremely severe disease states with impending
respiratory failure. One of the key points in the treatment of ARDS is the early
identification of patients with respiratory involvement so that mechanical ventilation
can be initiated before they reach an extreme state of respiratory failure.

The heterogeneous distribution of lung disease in patients with ARDS makes
mechanical ventilation a challenge to the intensive care specialist. In typical
ARDS, gravitationally-dependent lung regions exhibit dense alveolar and interstitial
inflammatory infiltrates, edema, cellular debris, atelectasis and consolidation,
while non-dependant regions are relatively spared (Figure 1)11. In a healthy lung with homogeneous surface
tension, tidal volume is evenly distributed among the various lung segments.
In patients with ARDS, however, the tidal volume follows the path of least impediment,
with a tendency to overdistend the more compliant alveoli (non-dependent) while
failing to recruit the less compliant alveoli in the dependent areas. In addition
to being heterogeneous, lung pathology in ARDS is also dynamic12,
as areas with relatively adequate compliance can become poorly compliant in
a matter of hours, as the syndrome evolves rapidly.

Mechanical ventilation
for ARDS is much more than a mere support modality used to buy time until resolution
of the lung disease process. We now know that the choice of ventilation strategy
is capable of influencing the progression of the lung disease, with more favorable
outcomes resulting from protective strategies. Similarly, non-protective ventilation
strategies are associated with less favorable physiological outcomes and increased
mortality5, 13-15.

Tidal volume (Vt)

The use of an inadequately
high Vt in experimental models is capable of promoting pulmonary injury even
in healthy lungs16. In experimental ARDS models, a Vt that has traditionally
been considered adequate, such as 10 ml/kg, has been associated with progression
and worsening of the pulmonary injury17. This occurs because, in
low pulmonary compliance states, the introduction of moderate or high Vt can
lead to alveolar overdistension, marked by the upper inflection point on the
volume-static pressure relationship curve (Figure 2), resulting in the so-called "volutrauma". Based on
this principle, Amato and colleagues have demonstrated significantly reduced
28-day mortality in ARDS patients treated with an open lung strategy consisting
of a Vt of less than 6 ml/kg and PEEP set above the lower inflection point.
However, two other studies, employing reduced Vt only 18,19 failed
to show any benefit from this strategy in patients with ARDS. More recently,
a North American multi-center study involving 861 patients with ARDS15
showed a 22% reduction in mortality among patients treated with reduced Vt (6
ml/kg) in comparison with traditional Vt (12 ml/kg). The discrepancies between
results of the various multi-center studies are related to significant methodologic
variations, such as different Vt values employed for the intervention and control
groups (Figure 3). Only studies with a sufficient difference in Vt between
the reduced volume and the control groups 5,15 yielded positive results.

To this date, no
clinical studies have tested the hypothesis that reduced Vt would be beneficial
in the pediatric population. However, considering that the recommendation to
use reduced Vt has a strong physiological, experimental and clinical support
(in adults), pediatric patients with ARDS should be given mechanical ventilation
with a Vt equal to or less than 6 ml/kg until data specific to this population
become available.

Positive end-expiratory
pressure (PEEP)

In ARDS, alveoli
in the dependent lung regions exhibit greatly reduced compliance in comparison
with non-dependent alveoli. As such, during every expiration the more dependent
alveoli reach a critical closing volume, which results in alveolar collapse.
This is followed by reopening of these collapsed alveoli during inspiration.
The cyclical repetition of alveolar collapse and re-opening generates shearing
forces capable of causing tissue damage (atelectrauma). The use PEEP is primarily
aimed at avoiding the collapse of the less compliant alveoli at the end of expiration.
Excessive use of PEEP increases the risk of pneumothorax, generates hyperinflation
of certain pulmonary segments and can cause adverse hemodynamic effects by increasing
intra-thoracic pressure and thus reducing venous return (pre-load). However,
the application of inadequately low PEEP levels during mechanical ventilation
provokes cyclic alveolar collapse and re-opening, resulting in atelectrauma.

The use of adequate
levels of PEEP that target sufficient lung volume maintenance during is associated
with favorable physiological outcomes13,16,17. As has been mentioned
above, Amato and colleagues5 have demonstrated a reduction in 28-day
mortality in patients ventilated with a Vt lower than 6 ml/kg and PEEP level set
above the lower inflection point. It is impossible to discern whether the observed
effects5 are attributable to the limited Vt, the use of sufficient
PEEP or both (Figure 3). However, strategies that apply sufficient PEEP while
avoiding alveolar over distension can prevent the generation of pro-inflammatory
mediators (biotrauma) that may adversely affect the progression of the pulmonary
lesion17,20 , as well as damage remote organs if these substances were
to enter into circulation21. Despite the protective role of PEEP having
been systematically documented in laboratory studies, the North American multi-center
clinical trial of patients treated with a high pulmonary expiratory volume and
low FiO2 compared with patients treated with a low pulmonary expiratory
volume and high FiO2 was recently terminated due to futility after
the inclusion of 550 patients22.

In clinical practice,
pediatric patients with ARDS should be ventilated with PEEP that is capable
of maintaining adequate pulmonary volume at the end of expiration. This value
is generally above 8 cm H2O and below 20 cm H2O, other
than in exceptional cases. Positive end-expiratory pressure should be progressively
increased (in 2 to 3 cm H2O increments) to optimize oxygenation (saturation
between 90 and 95% with FiO2< 0.5) and pulmonary inflation
checked with chest radiographs or computerized tomography. Patients with severe
anasarca or other restrictive lesions of the chest (circumferential burns),
as well as patients with excessive abdominal pressure, may require higher PEEP
levels.

A strategy that limits
Vt while at the same time applies an ideal PEEP, generally results in a reduction
in minute volume and hypercapnia, even when the respiratory rate is increased17.
Strategies with permissive hypercapnia (controlled hypoventilation), in which
an elevation in PaCO2 up to approximately 80 torr is accepted as
long as pH is kept above 7.25, are well tolerated by adults23 but
may have adverse effects24 and have not been adequately tested with
children. In our clinical practice, pediatric patients with ARDS who develop
significant hypercapnia when protective ventilation is initiated (elevated PEEP
with limited Vt) are promptly started on high frequency oscillatory ventilation.

Ventilation mode

Modern conventional
mechanical ventilators offer an increasing array of ventilation modes for use
in patients with ARDS. Conceptually, however, most ventilation modes used in
ARDS are similar in that they are cycled by time and limited by volume or pressure.
A mode that is cycled by time and limited by volume implies that the cycle (inspiration
and expiration) is controlled by time (inspiratory time and breath rate), and
that during the inspiratory phase of the cycle a certain pre-determined volume
is administered. A mode that is cycled by time and limited by pressure implies
that the cycle (inspiration and expiration) is controlled by time (inspiratory
time and breath rate), and that during the inspiratory phase of the cycle a
certain pre-determined pressure is administered. In volume-limited ventilation,
the Vt administered during each inspiration generates a certain airway pressure
(which is measured and controlled in current ventilators). Similarly, in pressure-limited
ventilation, the application of a specific pressure gradient between the ventilator
and the airway results in the generation of a certain Vt that can be measured
and controlled. Regardless of the ventilation mode used, it is important to
emphasize that no one conventional ventilation mode has been shown to be clinically
superior to another in the management of patients with ARDS, as long as the
principles of protective ventilation are respected.

Considering that
precise Vt control is a very important factor in ARDS support, time-cycled volume-limited
modes are preferred by the most of intensive care specialists nowadays. In time-cycled
volume-limited ventilation (controlled, assist-controlled, intermittent mandatory
or intermittent mandatory with pressure support) the operator defines the exact
Vt to be administered by each mandatory ventilator cycle. The pressure measurements
generated by this set volume at the end of inspiration (dynamic) or after a
pause (static or plateau pressure) are indicators of pulmonary compliance in
ARDS. A peak inspiratory pressure which increases over time for a fixed volume
generally indicates worsening compliance. In an analogous manner, a reduction
in peak inspiratory pressure generally indicates an improvement in compliance.
Volume-limited ventilation traditionally generates a triangular pressure waveform,
in contrast with the rectangular waveform of pressure-limited ventilation (Figure 4). As the area under the pressure curve reflects mean
airway pressure, volume-limited modes (triangular waveforms) generally have
a slightly lower mean airway pressure than pressure-limited modes (rectangular
waveform). Modern ventilators like the Servo 300, however, offer a mode known
as pressure regulated volume control (PRVC), in which the shape of the pressure
waveform of this volume-limited mode is similar to the rectangular format of
the pressure-limited mode. As such, the use of PRVC has been gaining wide acceptance
in the management of patients with ARDS.

Fluid administration

In caring for patients
with ARDS, the intensive care specialist must ponder the quantity and quality
of fluids that will be administered. For rapid intravascular expansion, the
decision on the administration of colloids or crystalloids depends, to a certain
extent, more on the personal convictions of the individual intensive care specialist
than on established scientific facts. Those who prefer to give colloids justify
the practice by the fact that these substances are capable of producing greater
intravascular expansion per unit of volume, remain longer within the intravascular
space and increase colloid osmotic pressure. Those who choose crystalloids do
so because these are cheaper, more readily available, are capable of promoting
intravascular expansion equivalent to colloids (when infused volumes are adjusted)
and because they do not increase oncotic pressure in the pulmonary interstitium
should they extravasate from the capillaries, as can occur with colloids. Controlled
clinical studies are inconclusive on the superiority of colloids or crystalloids.
Therefore, the choice of fluids for rapid intravascular expansion should be
based on the patient's needs at any given moment, taking into account the type
of loss that has occurred, the urgency to resuscitate and the availability of
fluids, in addition to plasma colloid osmotic pressure.

The amount of fluids
administered to patients with ARDS is also the subject of debate. There is no
question that patients in shock or with severe hypovolemia, both risk factors
for ARDS, should be aggressively resuscitated, generally with infused volumes
that exceed 60 ml/kg during the first hour, since this practice reduces mortality
and is not associated with an increased incidence of ARDS25. Once
hemodynamic stability is achieved in the patient with ARDS, the intensive care
specialist should concentrate efforts on minimizing the capillary leak and pulmonary
edema accumulation that occur in ARDS. Studies in animal models of acute lung
injury indicate that the fluid accumulation in the lung can be attenuated by
reducing left atrial pressure26. This strategy of limiting fluid
administration is also supported by some clinical studies of patients with ARDS27,28.
The North American study group involving 24 hospitals (ARDS Network) organized
for the study of ARDS is currently conducting a controlled multi-center, randomized
study of "conservative" versus "liberal" fluid administration. Until the results
of this study become available, a sensible recommendation is to maintain intravascular
volume at the lowest level that permits the maintenance of adequate systemic
perfusion, assessed by renal and cardiac functions and by the acid-base balance.

Non-conventional ventilation

High frequency ventilation (HFV)

Mechanical ventilation techniques that employ supra-physiologic frequencies,
generally between 60 and 900 cycles per minute, are collectively known as HFV.
Various types of HFV are available, although only high frequency positive pressure
ventilation (HFPPV), high frequency jet ventilation (HFJV) and high frequency
oscillatory ventilation (HFOF) have gained significant penetration into clinical
practice. Clinical studies of HFPPV and HFJV compared with conventional ventilation
were disappointing and resulted in the virtual abandonment of these techniques
for the management of patients with ARDS29. The use of HFOV, however,
is strongly supported by studies of experimental ARDS models 17,30,31
and has sufficient clinical evidence to justify its use under selected circumstances32-34.

In HFOV, tidal volumes that approximate dead space volume are actively
pushed into and pulled out of the airway at a frequency of between 3 and 15
hertz (180 to 900 cycles per minute) by means of a piston or diaphragm. The
proposed advantage of HFOV is that, due to the minute tidal volume of each cycle,
the method is capable of ventilating patients with ARDS within a "Safety Zone"
that avoids both alveolar overinflation during inspiration and cyclical closure
and re-opening of the alveoli during expiration (Figure 2). Oxygenation and ventilation are controlled independently
during HFOV. Controlling the mean airway pressure determines the state of pulmonary
inflation and, consequently, oxygenation. Controlling the amplitude of oscillation
indirectly determines the tidal volume of each cycle and, consequently, the
efficacy of ventilation (CO2 elimination). As such, HFOV is ideal
in situations when the patient with ARDS has worsening pulmonary compliance
with hypoxemia, requiring a reduction in the Vt of conventional ventilation
in order to avoid elevated peak inspiratory pressures, which leads to significant
respiratory acidosis. The realization that HFOV can favorably influence the
pulmonary inflammatory milieu in experimental models17,31,35 as well
as reduce the incidence of chronic lung disease 32,34 has been responsible
for the enthusiasm about this method and for its increasingly early deployment
in patients with ARDS. The use of HFOV in pediatric patients with ARDS requires
deep sedation and neuromuscular relaxation, since spontaneous respiratory movements
interfere with gas flow mechanics in this modality.

Non-invasive ventilation

The application of
non-invasive positive pressure (CPAP or BiPAP) in patients with ARDS is capable
of attenuating, albeit temporarily, the reduction in residual functional capacity
responsible for the progressive hypoxemia that is characteristic of this pathology.
The use of CPAP results in a transient improvement in oxygenation, yet it is
not associated with reductions in the need for intubation, length of hospital
stay or mortality of patients with ARDS10. The use of CPAP for ARDS
is also associated with an increased incidence of adverse effects10.
As such, the use of CPAP in the prophylaxis or treatment of patients with ARDS
is not recommended.

Partial liquid
ventilation

Partial liquid ventilation
(PLV) is a technique that employs perfluorochemical substances capable of dissolving
large quantities of oxygen and carbon dioxide. In PLV, the lung is filled with
a liquid perfluorocarbon via the endotracheal route so as to occupy the functional
residual capacity, while volumes of gas are introduced through a conventional
ventilator during each inspiratory cycle36. The potential advantage
of PLV in ARDS stems from the fact that when the lung is occupied by liquid
it has a uniform surface tension, in contrast to the heterogeneous surface tension
typical of ARDS. This occurs because the perfluorocarbon forms a liquid-liquid
interface at the alveolar surface, in contrast to the liquid-gas interface found
in conventional ventilation. A medical-grade perfluorocarbon called perflubron
(C8-F17-Br1) has been successfully tested in the treatment of experimental acute
lung injury. We now know that perflubron, as well as other perfluorocarbons
that were considered biologically inert, have anti-inflammatory biological effects
and protect cellular components against oxidative damage37-41. However,
the enthusiasm for PLV in the laboratory has not been repeated in the clinical
arena. Controlled studies of children and adults with ARDS and acute lung injury
have not demonstrated PLV to be superior to protective conventional ventilation42.
Further studies are necessary to test the impact of this method in specific
clinical situations, such as progressive pulmonary recruitment (liquid PEEP)
and intrapulmonary drug administration or viral vectors for genetic therapy.
This treatment is not currently available for use outside of the research laboratory
environment and cannot be recommended for the treatment of ARDS.

Drug-based therapies

Surfactant replacement

The success of surfactant therapy with premature newborns, associated with
the fact that the surfactant system is dysfunctional in patients with ARDS,
led intensive care specialists to speculate on a possible role for this substance
in the treatment of this syndrome. However, the use of surfactant in adult patients
has not been shown effective at improving oxygenation, shortening duration of
mechanical ventilation or reducing mortality in a controlled clinical study43.
Possible explanations for this include the administration method employed (aerosol),
which results in less than 5% of the dose, as well as the type of surfactant
used (a phospholipid preparation without surfactant proteins). New surfactant
preparations extracted from bovine lungs that contain phospholipids, neutral
lipids and hydrophobic surfactant proteins types B and C are considered to be
more effective and are being tested in patients with ARDS for administration
via endotracheal tube44. Until definitive studies are available,
the routine use of surfactants in patients with ARDS cannot be recommended,
being reserved for non-routine use in special situations when recruitment of
lung segments cannot be achieved with more conventional methods. Even in these
situations, the use of surfactants in ARDS is questionable.

Nitric oxide

Nitric oxide is a
potent vasodilator that can be administered via inhalation causing pulmonary
vascular relaxation. Inhaled nitric oxide reaches the alveolus where it enters
into direct contact with the pulmonary vasculature. During its migration through
the wall of the blood vessel, nitric oxide causes direct relaxation of the muscular
layer, before reaching the vascular lumen. Nitric oxide is then rapidly deactivated
by binding with hemoglobin, resulting in the formation of methemoglobin and
avoiding the undesirable effect of systemic vasodilation. The pulmonary vasodilatory
effect of nitric oxide associated with the fact that the target vasculature
is adjacent to the ventilated areas of the lung results in not only a decrease
in pulmonary vascular resistance, but also in attenuation of ventilation-perfusion
mismatch, thus improving oxygenation. The use of nitric oxide in newborns with
pulmonary hypertension has achieved great clinical success, reducing morbidity
and the need for extracorporeal support45. However, its use in patients
with ARDS has been disappointing. Despite producing a transient improvement
in oxygenation, this benefit is of short duration and does not offer any objective
gains. The use of nitric oxide in ARDS does not reduce mortality or the duration
of mechanical ventilation46 and cannot therefore be routinely recommended
in clinical practice. Nitric oxide can be used as a therapy of exception for
temporary rescue of patients with hypoxemia that is refractory to more conventional
interventions.

Corticosteroids

The fact that acute pulmonary damage in ARDS is primarily the result of
an aggressive inflammatory process has lead intensive care specialists to consider
anti-inflammatories in general, and corticosteroids in particular, as logical
therapeutic alternatives. The use of corticosteroids, however, does not prevent
the development of ARDS47 nor is it beneficial when employed during
the initial phase of its clinical course48. Corticosteroids appear
to have some benefit when used during the later stages of the disease, which
are marked by the reorganization of the acute inflammatory infiltration and
fibrosing alveolitis49. Currently, a multi-center randomized controlled
North American study (ARDS Network) is being conducted to evaluate the efficacy
of high doses of methylprednisolone during the later phases of ARDS. However,
due to the fact that treatment with high doses of corticosteroids can increase
the risk of secondary infections and other adverse effects, their routine use
in ARDS treatment cannot yet be recommended. In our clinical practice, we reserve
the use of corticosteroids as a rescue therapy in severe ARDS cases during the
later phase of the disease (third or fourth week) when there is no progress
in reducing the level of ventilatory support.

Other inflammation
control agents

Despite having produced
promising results in experimental models of acute lung injury, the use of non-steroidal
drugs with anti-inflammatory effects, such as indomethacin, ibuprofen, procysteine,
lisofylline and ketoconazole, have not been shown beneficial in the clinical
arena50. The use of these drugs for the treatment of patients with
ARDS, therefore, cannot be recommended.

Extracorporeal membrane oxygenation (ECMO)

Extracorporeal membrane oxygenation consists of the use of a complex circuit
of vascular cannulae, tubes, pumps, oxygenator, heat exchanger and monitoring
systems used to provide respiratory support (in the case of veno-venous ECMO)
or cardiorespiratory support (in the case of veno-arterial ECMO). To date, approximately
25,000 patients have undergone ECMO throughout the world with an overall survival
rate of approximately 75%. The vast majority of these patients (17,000) were
neonates with refractory pulmonary hypertension, while the experience in pediatric
and adult cases of ECMO for treatment of ARDS is limited to approximately 3,000
cases (personal communication, ECMO Registry of the Extracorporeal Life Support
Organization (ELSO), Ann Arbor, Michigan, November, 2002). Extracorporeal membrane
oxygenation reduces the mortality of newborns with persistent pulmonary hypertension
secondary to meconium aspiration syndrome (94% survival), but has yielded more
modest results in older children with ARDS (52% survival). Clinical studies
of the use of ECMO or an extracorporeal carbon dioxide elimination system with
adults suffering from ARDS did not reveal any benefits in terms of reduced mortality51.
However, the outcome results for ECMO therapy in the international extracorporeal
life support registry for pediatric patients with ARDS refractory to all other
forms of treatment, and also in our personal practice, strongly suggest that
this technique is of value in selected cases.

Indications for ECMO in ARDS cases are restricted to patients with the
highest degree of acute pulmonary failure that is potentially reversible, yet
unresponsive to all less invasive conventional or non-conventional treatment
methods. The basic premise for indicating ECMO is that the death of the patient
is presumably imminent without the use of this technology. During the last 7
years, 22 of these pediatric patients with extreme respiratory failure underwent
ECMO for treatment of ARDS at the Children's Hospital of Buffalo, with a survival
rate of 54%. These results are compatible with those from other centers of excellence
in North America and are a great impediment to the realization of randomized
trials. In common with us, the majority of centers that utilize this treatment
method consider unethical to allocate patients who are candidates for ECMO to
a control group without intervention, since such patients have a projected mortality
rate of nearly 100%.

Positioning therapy

The simplicity and low cost of the use of prone positioning, associated
with reports of improvements in oxygenation in 60 to 70% of patients with ARDS
has made this therapeutic method popular. A number of different mechanisms have
been suggested to explain this effect in patients placed in the prone position,
such as an improvement in the ventilation-perfusion relationship52,
increased pulmonary volume at the end of expiration53 and regional
ventilation changes associated with mechanical alterations of the thoracic wall54.
However, as has been demonstrated above, improvements in oxygenation do not
necessarily translate to reduced mortality in ARDS15. Recently, Gattinoni
and colleagues55 reported the results of a multi-center, controlled
study in which patients with ARDS were randomized to receive either conventional
treatment (supine position) or treatment in the prone position for 6 or more
hours per day for 10 days. In this study, despite causing an improvement in
oxygenation, the use of the prone position did not result in a reduction in
mortality55. A number of different theories may explain these findings.
The simplest is that the use of the prone position indeed does not prevent or
attenuate the advance of pulmonary injury in patients with ARDS. On the other
hand, despite including 304 patients, this study probably did not have sufficient
statistical power to reveal differences between groups, since clinical studies
of ARDS are marked by heterogeneous characteristics demanding large sample sizes.
The patients randomized to the prone group assumed the position for approximately
7 hours per day (or just 30% of the time) and for a maximum of 10 days. It is
possible that the limited duration of exposure to the prone position could explain
the failure of this strategy.

A multi-center study of pediatric patients with ARDS involving the use
of the prone position for the greater part of the day and until resolution of
the respiratory failure is in progress in tertiary ICUs in North America. Until
concrete results are available, the recommendation to place patients with ARDS
in the prone position in an attempt to improve oxygenation and allow exposure
to lower concentrations of oxygen appears to have a reasonable theoretical foundation
and few risks or costs associated with it.

Prevention and early diagnosis of intercurrent infections

As ARDS patients require invasive technology, such as vascular and urinary
catheters, endotracheal intubation and mechanical ventilation for prolonged
periods of time, they are often the target of secondary infections, especially
pulmonary infections. Early diagnosis and precise treatment of these infections
is extremely important, since secondary pneumonias act as an additional pro-inflammatory
insult. Radiologic diagnosis of secondary pulmonary infections in patients with
ARDS is complicated by the fact that these patients exhibit pre-existing radiologic
abnormalities. Clinical diagnosis also presents challenges, since symptoms such
as fever, leukocytosis and increased tracheal secretions may already be part
of the basic disease process. In clinical practice, early diagnosis may be achieved
by integrating radiologic alterations, appearance and cellularity of tracheal
secretions and routine cultures (tracheal aspirate, broncho-alveolar lavage
and blood culture).

As with other nosocomial infections, prevention is the best method of reducing
the risk of secondary pulmonary infections. Immunosuppressed or contagious patients
should be isolated and the use of universal contact precautions and frequent
hand washing are simple and highly effective measures. Criteria-based antibiotic
therapy guided by the antibiogram of organisms isolated by cultures or on local
epidemiological data also plays an important role in the prevention of secondary
infections.

Analgesia and sedation

The comfort of patients with ARDS during their stay in the ICU should occupy
a prominent position in the therapeutic strategy. Patients in the acute phase
of the disease should receive infusions of medications to reduce the emotional
stress and physical discomfort inherent to the pathology, as well as in anticipation
of painful procedures. Our practice is to maintain patients with ARDS on continuous
sedation and pain relief, with these needs being reevaluated on a daily basis.
Infusions of midazolam (0.1 mg/kg/h) and fentanyl (2 µg/kg/h) are used in the
majority of patients and doses are adjusted according to clinical requirements,
with doses of 10 times higher than the original not being uncommon by the third
week of the clinical course. Patients subjected to permissive hypercapnia or
HFOV require the infusion of neuromuscular blocking agents, such as vecuronium
(0.1 mg/kg/h). Patients with highly compromised pulmonary mechanics and during
the acute phase of the disease also often require neuromuscular blocking agents.

Nutritional Support

Patients with ARDS have an elevated daily caloric requirement as a function
of the stress of trauma, sepsis, surgery or the inflammatory process that accompanies
the lung injury in ARDS. These patients require prompt institution of parenteral
or enteral nutrition since a caloric deficit can result in alterations of the
defense mechanisms, as well as delay lung healing. We prefer continuous enteral
nutrition via the naso-duodenal route, as soon as technically feasible. Total
parenteral nutrition should be started immediately for patients who demonstrate
intolerance or contraindications to enteral nutrition. Among potential complications
of parenteral nutrition, it should be noted that hypercapnia can occur as the
result of an excessive carbohydrate load through alterations in the respiratory
quotient.

Psychological support

The psycho-social needs of the family and the patient with ARDS are extremely
complex. Even in adequately sedated patients, factors such as anxiety over the
uncertainty of the clinical outcome, the impossibility of speech due to the
artificial airway, the occasional pain due to invasive procedures and the changes
to the awake and sleep cycles, among others, cannot be neglected by the medical
team. Attention must be afforded to explain to the patient (whenever possible)
and the family all the diagnostic and therapeutic procedures and also the natural
course and prognosis of the condition. It is common for adolescent patients
and older children in the recovery phase of ARDS to exhibit delirium, depression
or altered circadian patterns during prolonged hospitalization in an ICU environment.
Such manifestations often require the involvement of a psychiatric consultant
to monitor patients during recovery and after hospital discharge. The multidisciplinary
medical team should always be alert to and available for the psychological needs
of ARDS patients and their families, particularly because ICU hospital stays
due to severe ARDS are prolonged and generally marked by oscillation between
periods of frustration and optimism.

Monitoring the patient

Patients with ARDS represent a relatively severe stratum of the population
of a tertiary ICU. As such, these patients require a high level of monitoring
so that data can be obtained and integrated in real time for individual strategic
treatment planning. Patients with ARDS routinely require an arterial catheter
for continuous arterial pressure monitoring and for obtaining serial arterial
blood gas analysis. A central venous catheter with two or three lumens is used
for the administration of fluids and drugs and also for continuous measurement
of the central venous pressure. A urinary catheter permits the precise measurement
of urinary output and control of the fluid balance. Continuous pulse oximetry
is used for real time assessment of oxygenation. Analysis of exhaled carbon
dioxide curves provides a continuous data for inferring ventilation, pulmonary
perfusion and dead space. Respiratory monitoring via graphic interfaces allows
for the real time visualization of a series of respiratory parameters derived
from pressure, flow, time and volume. Serial echocardiography is a good method
for monitoring the degree of atrial filling (preload) as well as the cardiac
function resulting form different combinations of inotropic drugs and states
of intravascular expansion. In our experience, a pulmonary artery catheter (Swan-Ganz)
has little use in patients with ARDS with no primary cardiac involvement. The
use of such catheters rarely alters the management based on data obtained from
the auxiliary technologies described above. Patients receiving continuous neuromuscular
blockade should be monitored with nerve stimulators to avoid the unnecessary
use of exaggerated drug doses.